Itch, also known as pruritus, is defined as the unpleasant sensation that elicits the desire or reflex to scratch. Persistent itching is an importat component of many cutaneous diseases or system disorders such as contact dermatitis, chronic renal insufficiency and cholestatic liver diseases. The chronic itching can be very devastating and significantly affect the patients' quality of life. Since the molecular and cellular mechanisms of itch sensation are largely unknown, there are only limited treatments for most of the patients. Recent studies have shown that members of the Mrgprs family serve as new itch receptors mediating the itch sensation elicited by multiple pruritogens. In this proposal, I will use molecular, genetic, behavioral and pharmacological approaches to investigate the role of Mrgprs in mediating different types of itch sensation. This proposal consists of 3 specific aims. Specific aim 1 will determine whether Mrgprs are involved in mosquito bite-induced itch. In this aim, I will isolate the pruriceptive component in mosquito saliva and test the hypothesis that it activates Mrgprs directly. Specific aim 2 will test whether antagonizing Mrgprs has an antipruritic effect in chronic itch conditions. For this purpose, I have established a humanized mouse itch model. I will use this model to examine whether the treatment with Mrgprs antagonist can block the chronic itch sensation. Specific aim 3 will test the idea that Mrgprs not only mediate the itch sensation in the skin, but also in the airway. Successful completion of the proposed studies will provide insight into the periphery mechanisms underlying itch sensation and new therapeutic strategies to treat chronic itch.